216-OR: O-GlcNAc Transferase in the Ventromedial Hypothalamus Regulates Lipid Metabolism through Fat Depot–Specific Sympathetic Innervation

Abstract

The ventromedial hypothalamus (VMH) is a primary site that initiates counter-regulatory response and regulates food intake, maintaining glucose and lipid homeostasis. Known as a nutrient sensor and metabolic regulator, O-linked β-D-N-acetylglucosamine modification (O-GlcNAcylation) of intracellular proteins is catalyzed by O-GlcNAc transferase (OGT). How O-GlcNAc signaling in the VMH regulates whole-body metabolism remains unknown. Here, using the mouse model with VMH neuron-specific OGT deletion (VOK), we report that OGT is a nutrient sensor in VMH neurons that primarily regulates lipid metabolism. VOK mice show increased body weight and adiposity as well as reduced energy expenditure. OGT deletion in VMH neurons has no significant effects on food intake, physical activity, substrate utilization, glucose tolerance or insulin sensitivity. Lipolysis in subcutaneous and visceral white adipose tissues (WATs) is reduced in VOK mice, indicated by reduced activation of hormone-sensitive lipase (HSL) via cAMP-dependent protein kinase (PKA). In addition, VOK mice have lower serum glucagon and norepinephrine levels and show impaired depot-specific sympathetic innervation to WATs. These data reveal that O-GlcNAc signaling in VMH neurons specifically controls lipid metabolism through depot-specific sympathetic innervation. Disclosure Q. Wang: None. B. Zhang: None. Y. Yang: None. J. Mi: None. G. Tian: None. Q. Ong: None. X. Yang: None. Funding American Diabetes Association (1-19-IBS-119 to X.Y.); National Institutes of Health (R01DK089098, R01DK102648)